(M1430-10-59) High Drug Load Metformin ER 1000 mg Tablets Processed via Roller Compaction in Combination with High Molecular Weight HPC

Purpose: Before tableting a powder, different granulation processes are often needed to increase powder properties (flowability, bulk density). Especially high drug load formulations as Metformin HCl extended-release matrix tablets are often prepared by melt granulation due to high DL ( >65%)/ high dosed ( >1000 mg) and the need for sufficient tensile strength (TS > 1.2 MPa) for subsequent downstream processing e.g., coating and packaging. To increase throughput, reduce production cost and complexity of the process, a roller compaction (RC) process was introduced to produce tablets with similar dissolution behavior as the market formulation Siofor XR ® and sufficient tensile strength using HPC-VH FP.Further recompactability/workhardening of the granules as well as release and swelling properties to assess potential gastroretentive properties were investigated.

Methods: Materials: HPC-VH FP (Nippon Soda, Japan), Metformin HCl(Aarti Drug Ltd.), Magnesium Stearate (Peter Greven,Nederland C.V.) Powder mixture for RC: All formulations contained 0.5% Magnesium Stearate as lubricant added after the first mixing process. HPC-VH FP and Met were mixed using a tubular mixer for 10 minutes. After 10 minutes the magnesium stearate was added and mixed for an additional minute. RC process: RC was performed with a Gerteis MiniPolygran at 2 mmgap, 1 U/min and granulated through a 2 mm sieve. The specific compaction force was varied from 3 kN/cm to 9 kN/cm. Particle size was determined via dynamic image analysis and expressed as x area . The powder flowability was compared using angle of repose and bulk density. Tablets: The tablets were compressed using the Styl’one classic with a compaction profile, mimicking the compaction on a Fette 102i equipped with oval, shallow concave 19 x 9.5 mm tooling. TS of tablets were checked after 24 h. Dissolution: Dissolution was performed using the USP 2 apparatus, over 8 hours in 900 mL 0.1 M HCl at 37 °C and 75 RPM. The analysis was done using a HPLC UV method. Swelling: The thickness of the different layers (diffusion, swelling and dry core) was determined after 5, 15 and 30 min of immersion in dissolution medium using a texture analyzer, recording the force/displacement curves at constant speed of the intrusion probe of 0.1 mm/s.

Results: All RC granules showed a decrease in angle of repose and an increase in bulk density. The particle sizedistribution shifted towards larger sizes with increase of specific compaction force. The various specificcompaction forces resulted in tablets of tensile strengthsranging from 0.8 – 1.6 MPa. As expected, higher specific compaction forces during RC, resulted in lower TS of the tablets. To increase tabletability, higher drug load RCgranules (90% Metformin HCl) were produced and subsequently mixed with HPC-VH FP and magnesiumstearate as an outer phase to a drug load of 65% of the final blend. The formed tablets showed higher tensile strength (1.53 MPa at 200 MPa) compared with final blends which did not contain a fraction of HPC-VH FP as an outer phase at a negligible impact on powder flow. The fine particle fraction of the 9 kN/cm 65% mixture was compacted a second time, leading to no change in particle size and little to no difference in TS of subsequently formed tablets. The dissolution profiles of all 65% DL tablets were similar to the commercially available Siofor XR® 1000 mg (F1 = 4.7 – 5.4, F2 = 74 - -81). Mechanistic differences seem to be primarily related in the thickness of the resulting diffusion layer at similar thickness of the swelling layer comparing 65% Met tablets and Siofor XR 1000 mg.

Conclusion: RC processing of mixtures containing 65% Met and 35% HPC-VH FP resulted in granules of good flow and subsequently in tablets with a similar dissolution behavior as the market formulation. TS of all tablets exceeded 1.0 MPa at 200 MPa, which should facilitate most downstream processes.
The higher drug load Met (90% DL) RC granules were successfully produced with sufficient flowability and showed an increase in TS to more than 1.5 MPa at 200 MPa. Due to the good plastic deformation behavior of HPC-VH FP (high molecular weight, high swelling, slow dissolving polymer) it was possible to compact the FPF a second time without workhardening at no change of dissolution or TS of the resulting tablets. The extent of swelling and the mechanical strength of the diffusion layer will be further assessed in order to assign gastroretentive properties according to size. Additionally, bioadhesive properties are subject of further investigations.

Acknowledgements: We thank Gerteis Maschinen + Processengineering AG, Switzerland for providing the Polygran roller compactor namely Paul Gerteis, Hartmut vom Bey and Michael Schupp.

Tabletability of 65% DL granules at different RC pressure. (IP = inner phase, amount of HPC-VH FP used to produce RC granules; OP = outer phase, HPC-VH FP content used to adjust DL of finished tablet)

Dissolution of HPC based 1000 mg Metformin extended-release tablets and market formulation Siofor XR 1000 mg